Improved steroid dehydrogenation process



United States Patent f 3,053,866 IMPROVED STEROID DEHYDROGENATION PROCESS John M. Chemerda, Metuchen, Edward W. Tristram,

Cranford, and David F. Hinkley, Plainiield, N.J., assignors to Merck & Co., Inc., Rahway, N.J., a corporation of New Jersey No Drawing. Filed Mar. 2, 1961, Ser. No. 92,754 16 Claims. (Cl. 260-397.45)

This invention relates to a process for the dehydrogenation of steroids and more particularly relates to an improved process for the production of 3-keto-16-methyl- 1,4-pregnadiene steroid compounds.

The recent discovery that the therapeutic properties of cortisone, hydrocortisone and similar related compounds may be remarkably enhanced by introduction of a double band between the l and 2 carbon atoms in the cyclopentanopolyhydrophenanthrene nucleus to form the corresponding 1,4-pregnadiene has stimulated wide interest in finding simpler and more economical methods for preparing such compounds. Likewise, where the compound to be so treated also lacks the essential double bond between the 4 and 5 carbon atom, i.e., a ring A saturated compound, it has been of interest to find improved methods for converting these compounds to their corresponding l,4pregnadienes as well.

One method of introducing double bonds in the A- ring of either a 3-keto-4-pregnene or a 3-keto-pregnane compound has been to contact the steroid compound with the dehydrogenating activity of selenium compounds such as selenium dioxide to form the corresponding 1,4-pregnadiene. However, this process has been found to be generally undesirable in view of the relatively low yields of these costly end products, i.e., yields in the order of about 40%.

Another method of introducing double bonds in the A-ring of these 3-keto-pregnanes and 3-keto-4-pregnenes has been to conduct the aforementioned selenium dioxide dehydrogenation process in the presence of acetic acid and metallic mercury or Zinc. Unfortunately, however, it has been found that the use of mercury or zinc in the selenium dioxide dehydrogenation of the A-ring of 3-keto steroids having a 16-methyl substituent results in no increase in yield over that of selenium dioxide alone, i.e., yields in the order of about 40%.

In accordance with the present invention, it has now been found that quite surprisingly, when selenium dioxide is employed as a dehydrogenating agent in the preparation of 3-keto-16-methyl-l,4pregnadiene compounds, yields in the order of about 65% are obtained when this process is carried out in the presence of certain auxiliary reagents, particularly mercury oxides, silver oxides and silver salts. Such compounds as mercuric oxide, mercurous oxide, silver oxide and silver nitrate have been found to be especially effective for this purpose. Thus, the present discovery provides a simple, effective and economical method for the production of l6-methyl ring-A unsaturated compounds in high yields.

The dehydrogenation process employing the aforementioned auxiliary reagents is conveniently conducted by bringing together the 3-keto-16-methyl starting material, selenium dioxide and the auxiliary reagent in the presence of any conventional solvent and particularly an inert organic solvent as for example t-amyl alcohol, t-butanol, dioxane, acetic acid, toluene, or the like at the reflux temperature of the mixture for a period of from about 10 to 24 hours and preferably for about -20 hours. However, it will be understood by those skilled in the art that the time and temperature may be varied depending upon the nature of the solvent employed. Because of its relatively high boiling point tertiary amyl alcohol has been substituents attached to the steroid nucleus, groups may be present at the 11 and 20 positions, hy-

droxy acetone side chain at the 17-position.

3,053,866 Patented Sept. 11, 19.62

found to be an excellent solvent in this dehydrogenation process. Thus, the reaction may be carried out at a higher temperature for a shorter period of time to avoid undue formation of by-products. It is desirable that the solvent be rendered substantially free of water prior to being used since it has been found that essentially anhydrous reaction conditions measurably raise the overall yield of the final product. Thus, by reducing the amount of Water in commercially available tertiary amyl alcohol from about 0.5% to 0.05%, the yield can be increased by as much as 2 to 4%. The drying of tertiary amyl alcohol can conveniently be achieved by contacting this solvent with metallic sodium or calcium hydroxide prior to its use in the dehydrogenation process.

When mercuric oxide is employed as the auxiliary agent it is desirable to use the yellow allotrope rather than the red allotrope in the dehydrogenation process since the yellow form .of the oxide has been found generally to produce somewhat higher yields of end product as compared with the red form.

The amount of starting materials employed in the process of this invention can readily be determined by those skilled in the art. It has been found, however, that from 0.5 to 4.0 grams of the auxiliary reagent per gram of starting material is a satisfactory range and preferably about 1.2 grams. The amount of selenium dioxide employed may also vary from about 0.5 to 4.0 grams per gram of starting material. Preferably about 1.2 grams of selenium dioxide per gram of steroid starting material is employed.

Upon completion of the reaction, the reaction product may conveniently be recovered by conventional means,

for example by first removing the solid precipitated selenium, as for example, by filtration, followed by dilution of the resulting filtrate with an inert organic solvent such as chloroform. When filtering to remove the selenium, it is useful to employ a filter aid such as infusorial earth. Super-Cel, made by Johns Manville is an example of such a filter aid. The chloroform solution is then desirably washed successively with sodium bicarbonate, hydrochloric acid and water to remove any unreacted selenium dioxide. The resulting chloroform phase is then separated from the aqueous phase and treated with a drying agent, as for example anhydrous sodium sulfate, to remove any traces of water. The final product may then conveniently be recovered by replacing the chloroform with a solvent in which the desired steroid is essentially insoluble. Thus, for example, by evaporating the chloroform to dryness and adding ether to the residual material,

. are the 21-acylates of 3-keto-16-methyl steroids and more particularly the ZI-acylates of 3-keto l6-methylpregnanes, 3-keto-l6-methy-l-4-pregnenes as well as 3-keto-l6 methyl steroids of the pregnane series having double bonds in other portions of the steroid nucleus, as for example 3-keto-l6-methyl-9( l l pregnenes and 3-keto-l6-methyl- 4,9(ll)-pregnadienes. The process can also be applied effectively to those steroids containing other functional Thus, keto drroxy groups at the 11 and 17 positions, and acyloxy groups at the 21 position. Alternatively, these oxygenated groups may be replaced by hydrogen at any or all of the above-mentioned carbon atoms except, however, that the starting material should contain an ester group at the 2l-position in order to avoid degradation of the d-ihy- The ester groups are preferably derived from organic oarboxylic acids, especially such acids containing from one to eight carbon atoms inclusive. Among such acids are formic, propionic, butyric, tertiary butylacetic, benzoic, and the like.

Representative of such steroids which may be dehydrogenated by the process of this invention are:

17u,21-dihydroxy 16a. methyl 9(11) pregnene-3,20-

dione 2l-acetate,

Hall-dihydroxy 16 3 methylpregnane 3,11,20-trione 21-acetate,

17a,21-dihydroxy 16B methyl 4 pregnene-3,11,20-

trione 21-acetate,

1l,8,17a,2l-trihydroxy 16p methyl 4 pregnene-3,20-

dione 21-acetate,

9a,-fluoro 1701,21 dihydroxy 16,8 methyl-4-pregnene- 3,11,20-trione ill-acetate,

9a-fll10lO-llfi;l7oz,21 trihydroxy 165 methyl-4-pregnene-3,20-dione 21-acetate,

1701,21 dihydroxy 16a methylpregnane 3,11,20-trione 2l-acetate,

1701,21 dihydroxy 16a methyl-4-pregnene 3,11,20-

trione 21-acetate,

11;3,17a,21 trihydroxy 16a methyl-4-pregnene-3,20-

dione ZI-acetate,

17a,21-dihydroxy 16a. methyl 4,9(11) pregnadiene- 3,20-dione 21-acetate,

9a fluoro 11,8,l7e,21-trihydroxy 16a methyl-4-pregnene-3,20-dione 21-acetate,

90c chloro 11,8,17e,21 trihydroxy-16a.-methyl-4-pregnene-3,20-dione 21-acetate, and the like.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that these examples are given for purposes of illustration and not of limitation.

Example 1 To 5 grams of 17a,21-dihydroxy-16a-methy1-9(11)- pregnene-3,20-dione 21-acetate in 190 ml. of commercial grade tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of yellow mercuric oxide. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel precoated funnel to remove the solid selenium. The Super- Cel cake is washed with three portions of 75 ml. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are backextracted with 100 ml. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of activated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. A 300 mg. portion assayed by U.V. shows a 67% yield of flail-dihydroxy 16a methyl-1,4,9( 11)-pregnatriene-3,20-dione ZI-acetate. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 17a,21-dihydroxy-16a.-methyl-1,4,9(11)- pregnatriene-3,20-dione 21-acetate in approximately 60 percent yield.

In accordance with the above procedure, but employing 90: fluoro 1lB,17a,21 trihydroxy 16a-methyl-4- pregnene-3,20-dione 21-acetate as the starting material, there is obtained 9a-fiuoro-ll/3,17u.,21-trihydroxy-16amethyl-l,4-pregnadiene-3,ZO-dione 21-acetate in similarly high yield.

Example 2 To 5 grams of 1704,2l-dihydroxy-16a-methyl-9(11)- pregnene-3,20-dione ZI-acetate in 190 ml. of anhydrous tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of yellow mercuric oxide. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel pre-coated funnel to remove the solid selenium. The Super-Cel cake is washed with three portions of 75 ml. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with ml. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of activated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 1701,21- dihydroxy 16a methyl 1,4,9(1l) pregnatriene-Ii,20- dione 21-acetate in approximately 65 percent yield.

In accordance with the above procedure, but employing 17a,21-dihydroxy-l6fi-methylpregnane-3,11,20 trione 21-acetate as the starting material, there is obtained 17a,2J1 dihydroxy 16B methyl 1,4-pregnadiene 3,11, 20-trione 21-acetate in similarly high yield.

Example 3 To 5 grams of ,21-dihydroxy-16a-methyl-9(11)- pregnene-3,20-dione 21-acetate in ml. of tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of silver nitrate. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel precoated funnel to remove the solid selenium. The Super-Cel cake is washed with three portions of 75 ml. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an additional 300 ml. of portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with 100 m1. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of activated charcoal for one hour at 25 C The mixture is filtered and Washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 17a, 21 dihydroxy 16oz -methyl 1,4,9(l1) pregnatriene-3,

20-dione 21-acetate in approximately 60 percent yield.

In accordance with the above procedure, but employing 11fl,17a,21 trihydroxy 16oz methyl 4 pregnene- 3,20-dione 21-tertiary butylacetate as the starting material, there is obtained 11B,170:,21-trihydroxy-16a-methyl 1,4 pregnadiene 3,20 dione 21 tertiary butylacetate.

Example 4 To 5 grams of 17a,21-dihydroxy-16a-methyl-9(11)- pregnene-3,20-dione ZI-acetate in 190 ml. of tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of mercurous oxide. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel precoated funnel to remove the solid selenium. The Super-Cel cake is washed with three portions of 75 m1. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an

additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with 100 m1. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of acti vated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 17a, 21 dihydroxy 16cc methyl 1,4,9(11) pregnatriene- 3,20-dione 21-acetate in approximately 65 percent yield.

In accordance with the above procedure, but employing 17a,2l dihydroxy 16a methyl 4,9'( 11) pregnadiene-3,20-dione 2l-acetate as the starting material there is obtained 17a,21-dihydroxy-16u-methyl-1,4,9(11)- pregnatriene-3,20-dione 211-acetate in similarly high yield.

Example 5 To 5 grams of 17a,2l-dihydroxy-16a-methyl-9(1l)- pregnene-3,20-dione 21-acetate in 190 ml. of tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of silver oxide. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel pre-coated funnel to remove the solid selium. The Super-Cel cake is washed with three portions of 75 ml. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodiumbicarbonate, an additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with 100 ml. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5' grams of activated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 17a, 21 dihydroxy 160a methyl 1,4,9(11) pregnatriene- 3,20-dione 21-acetate in approximately 60 percent yield.

In accordnace with the above procedure, but employing 1l;B,17o,21 trihydroxy 16B methyl 4 pregnene- 3,20-dione 21-acetate as the starting material, there is obtained 11,8,17a,21 trihydroxy 16B methyl 1,4- pregnadiene.-3,20-dione 21-acetate in similarly high yield.

Example 6 To 5 grams of 17u,21-dihydroxy-16u-methyl-9(11)- pregnene-3,20-dione 21-acetate in 190 ml. of tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of red mercuric oxide. The mixture is stirred at reflux temperature for 17 hours. The solution is cooled and filtered through a Super-Cel pre-coated funnel to remove the solid selenium. The Super-Cel cake is washed with three portions of 75 n11. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with 100 ml. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of activated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at C. in vacuo to obtain 17u,2'1-dihydroxy-l6a-methyl-1,4,9( 1 l -pregnatriene-3,20- dione 21-acetate in approximately 60 percent yield.

In accordance with the above procedure, but employing 17a,21-dihydroxy-l6a-methylpregnane-3,1 1,20-trione 21-propionate as the starting material, there is obtained 17a,21 dihydroxy-16a-methyl-1,4-pregnadiene-3,20-dione 2l-propionate in similarly high yield.

Example 7 Following the procedure of Example 3, but employing 9a chloro-l1B,17a,21-trihydroxy-16a-methyl-4-pregnene- 3,.20-dione 21-acetate as the starting material, there is obtained 9a-chloro-1 1 9,17a,'21-trihydroxy-16a-methyl-1,4- pregnadiene-3,20-dione 2-1-acetate in equally high yield.

Example 8 Following the procedure of Example 4, but employing 9u-fluoro 1711,21 trihydroxy 16B methyl-4-pregnene- 3,11-20-trione 21-acetate as the starting material, there is obtained 9a-fiuoro-l7a,2-1-trihydroxy-16,8-methy1-1,4- pregnadiene-3,11,20-trione 21-acetate in equally high yield.

Example 9 Following the procedure of Example 5, but employing 17a,21-dihydroxy a methyl-4-pregnene-3,11,20 trione 21-benzoate as the starting material there is obtained 17a,2l-dihydroxy 16a methyl-1,4-pregnadienee3,11,20- trione 21-benzoate in equally high yield.

Example 10 To 5 grams of 17u,21-dihydroxy-1*6a-methyl-9(11)- pregnene-3,20-dione 21-acetate in ml. of commercial grade tertiary amyl alcohol is added 6 grams of selenium dioxide and 6 grams of yellow mercuric oxide, selenium dioxide, 6 grams of mercury, and 0.8 ml. of acetic acid. The mixture is stirred at reflux temperature for '17 hours. The solution is cooled and filtered through a Super-Cel pre-coated funnel to remove the solid selenium. The Super-Cel cake is washed with three portions of 75 ml. of chloroform and the combined filtrate diluted to 500 ml. with chloroform. The chloroform solution is extracted with three portions of 300 ml. saturated solution of sodium bicarbonate, an additional 300 ml. portions of 0.1 N hydrochloric acid, and two 300 ml. portions of water. The combined aqueous layers are back-extracted with 100 ml. of chloroform and the aqueous layers discarded.

The combined chloroform layers are dried with 25 grams of anhydrous sodium sulfate and 5 grams of activated charcoal for one hour at 25 C. The mixture is filtered and washed with two 50 ml. portions of chloroform. The filtrate is evaporated to dryness at 75 C. in vacuo. A 300 mg. portion assayed by U.V. shows a 67% yield of 17ot,2l-dihydroxy-16a-methyl-1,4,9(11)- pregnatriene-3,20-dione Zl-acetate. Ether (45 ml.) is added to the crude gum and stirred two hours at 25 C. The slurry is aged for 12 hours at 5 C., filtered, washed with 15 ml. of ether and dried for two hours at 100 C. in vacuo to obtain 1706,21 dihydroxy 16a methyl- 1,4,9(11)-pregnatriene-3,20-dione Zl-acetate in approximately 40 percent yield.

Various changes and modifications may be made in the present invention, certain preferred embodiments of which are herein disclosed, without departing from the scope thereof; to the extent that these changes and modifications are within the scope of the appended claims, they are to be considered a part of this invention.

We claim:

1. A process for the preparation of 3-keto-16-methyl- 7 17u,2l-dihydroxy-1,4-pregnadiene 21-acylate compounds which comprises contacting a member selected from the group consisting of 3-keto-16-methyl-17a,21-dihydroxypregnane 21-acylate compounds and 3-keto-16-methyl- 1711,21-dihydroxy-4-pregnene 21-acylate compounds with selenium dioxide and a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

2. A process for producing 17a,21-dihydroxy-16-methy1-1,4,9(1-1)-pregnatriene 3,20 dione 21-acylate compounds which comprises contacting a 17a,21-dihydroxyr16-methyl-9(l1)-pregnene-3,20-dione 21-acylate compound with selenium dioxide and a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

3. A process for the preparation of 17a,21-dihydroxy- 16 methyl-1,4,9 (11)-pregnatriene-3,20-dione 21acetate which comprises contacting 17a,21-dihydroxy-16-methyl- 9(1l)-pregnene-3,20-dione ZI-acetate with selenium dioxide and a member selected from the group consisting of yellow mercuric oxide, mercurous oxide, silver oxide and silver nitrate in the presence of tertiary amyl alcohol.

4. The process according to claim 3 wherein the reaction is carried out under essentially anhydrous conditions.

5. A process for the preparation of 17a,2l-dihydroxyll-oxygenated 16 methyl 1,4 pregnadiene-3,20-dione 21-acylate compounds which comprises contacting a 170:,21 dihydroxy 11 oxygenated-16-methylpregnane- 3,20-dione 21-acylate compound with selenium dioxide and a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

6. A process for the preparation of 17a,21-dihydroxy- 11 oxygenated 16 methyl-1,4-pregnadiene-3,20-dione 21-acylate compounds which comprises contacting a 1711,21 d'ihydroxy 11 oxygenated-l6-methylpregnane- 3,20-dione 21-acylate compound with selenium dioxide and yellow mercuric oxide.

7. A process for the preparation of 17a,21-dihydroxy- 11 oxygenated 16 methyl-1,4-pregnadiene-3,20-dione 21-acylate compounds which comprises contacting a 17a,2l-dihydroxy l1 oxygenated-16-methyl-4-pregnene- 3,20-dione 21-acylate compound with selenium dioxide and a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

8. A process for the preparation of 90a -fluoro- 1'1 fl,l7a,21-trihydroxy 16a methyl-1,4-pregnadiene-3,20- dione ZI-acetate which comprises contacting a compound selected from the group consisting of 9a-fluoro-1 1,3,'17a,21- trihydroxy-l6u-methyl-pregnane-3,ZO-dione 21-acetate and 9ot-fluoro 11,8,17a,21 trihydroxy-l6u-rnethyl-4-pregnene- 3,20-dione 2l-acetate compound with selenium dioxide and a member selected from the group consisting of yellow mercuric oxide, mercurous oxide and silver oxide and silver nitrate in the presence of tertiary amyl alcohol.

9. The process according to claim 8, wherein the re-v action is carried out under essentially anhydrous conditions.

10. A process for the preparation of a 3-keto-l7a,2ldihydroxy-1,4-pregnadiene421-acylate compound which comprises contacting a corresponding saturated 3-keto steroid with selenium dioxide in a ratio of about 1 gram of steroid to 1.2 grams of selenium dioxide and heating in the presence of a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

11. The process of producing a 17a,21-dihydroxy-l6- methyl-1,4,9(11)-pregnatriene-3,20-dione 21-acylate compound which comprises contacting a 17a,21-dihydroxyl6-methyl 9(11) -pregnene-3,20-dione 2l-acylate compound with selenium dioxide in the ratio of about 1 part of steroid to about 1.2 parts of selenium dioxide in the presence of a member selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

12. A process according to claim 11, wherein the steroid and the selenium dioxide are heated in the presence of t-amyl alcohol.

'13. In a process for the dehydrogenation of steroids selected from the group consisting of 3-keto-l6-methyl- 17a,21-dihydroxy-pregnane 21-acylate compounds and 3-keto-16-rnethyl-17a,21-dihydroxy-4-pregnane 21-acylate compounds by means of selenium dioxide, the improvement which comprises carrying out the dehydrogenation in the presence of a compound selected from the group consisting of mercuric oxide, mercurous oxide, silver oxide and silver nitrate.

14. The process according to claim 13, wherein the reaction is carried out in the presence of tertiary amyl alcohol.

15. The process according to claim 14, wherein the reaction is carried out under essentially anhydrous conditions.

'16. An improved process for the preparation of 3-kcto- 16 methyl-17a,21-dihydroxy-1,4-pregnadiene 2l-acylate compounds which comprises contacting a 3-keto-16- methyl-17a,21-dihydroxy 21-acylate steroid of the pregnane series with selenium dioxide and a member selected from the group consisting of mercury oxides, silver oxides and silver salts.

No references cited. 

1. A PROCESS FOR THE PREPARATION OF 3-KETO-16-METHYL17A,21-DIHYDROXY-1,4-PREGNADIENE 21-ACYLATE COMPOUNDS WHICH COMPRISES CONTACTING A MEMBER SELECTED FROM THE GROUP CONSISTING OF 3-KETO-16METHYL-17A,21-DIHYDROXYPREGNANE 21-ACYLATE COMPOUNDS AND 3-KETO-16-METHYL17A,21-DIHYDROXY-4-PREGNENE 21-ACYLATE COMPOUNDS WITH SELENIUM DIOXIDE AND A MEMBER SELECTED FROM THE GROUP CONSISTING OF MERCURIC OXIDE, MERCUROUS OXIDE, SILVER OXIDE AND SILVER NITRATE. 